Solid Pharmaceutical Dosage Form

ABSTRACT

A solid pharmaceutical dosage form providing improved oral bioavailability is disclosed for inhibitors of HIV protease. In particular, the dosage form comprises a solid dispersion of at least one HIV protease inhibitor and at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, said pharmaceutically acceptable water-soluble polymer having a Tg of at least about 50° C. Preferably, the pharmaceutically acceptable surfactant has an HLB value of from about 4 to about 10.

This application is a continuation of U.S. patent application Ser. No.10/925,442, filed on Aug. 25, 2004, which claims priority from U.S.Provisional Application Ser. No. 60/498,412, filed on Aug. 28, 2003,both of which are incorporated herein by reference in their entireties.

The present invention is directed to a solid pharmaceutical dosage formcomprising at least one HIV protease inhibitor, and a process forpreparing same.

The virus causing acquired immunodeficiency syndrome (AIDS) is known bydifferent names, including T-lymphocyte virus III (HTLV-III) orlymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) orhuman immunodeficiency virus (HIV). Up until now, two distinct familieshave been identified, i.e., HIV-1 and HIV-2.

One of the critical pathways in a retroviral life cycle is theprocessing of polyprotein precursors by aspartic protease. For instancewith the HIV virus the gag-pol protein is processed by HIV protease. Thecorrect processing of the precursor polyproteins by the asparticprotease is required for the assembly of infectious virions, thus makingthe aspartic protease an attractive target for antiviral therapy. Inparticular for HIV treatment, the HIV protease is an attractive target.

A measure of the potential usefulness of an oral dosage form of apharmaceutical agent is the bioavailability observed after oraladministration of the dosage form. Various factors can affect thebioavailability of a drug when administered orally. These factorsinclude aqueous solubility, drug absorption throughout thegastrointestinal tract, dosage strength and first pass effect. Aqueoussolubility is one of the most important of these factors. Unfortunately,HIV protease inhibiting compounds typically are characterized by havingpoor aqueous solubility.

For a variety of reasons, such as patient compliance and taste masking,a solid dosage form is usually preferred over a liquid dosage form. Inmost instances however, oral solid dosage forms of a drug provide alower bioavailability than oral solutions of the drug.

There have been attempts to improve the bioavailability provided bysolid dosage forms by forming solid solutions of the drug. The term“solid solution” defines a system in a solid state wherein the drug ismolecularly dispersed throughout a matrix such that the system ischemically and physically uniform or homogenous throughout. Solidsolutions are preferred physical systems because the components thereinreadily form liquid solutions when contacted with a liquid medium suchas gastric juice. The ease of dissolution may be attributed at least inpart to the fact that the energy required for dissolution of thecomponents from a solid solution is less than that required for thedissolution of the components from a crystalline or microcrystallinesolid phase. If, however, the drug absorption in the gastrointestinaltract is slow the drug released from the solid solution may result in ahigh supersaturation and precipitate in the aqueous fluids of thegastrointestinal tract.

There is a continuing need for the development of improved oral soliddosage forms for HIV protease inhibitors which have suitable oralbioavailability and stability and which do not necessitate high vehiclevolumes.

The present invention provides a solid pharmaceutical dosage formcomprising a solid dispersion of at least one HIV protease inhibitor inat least one pharmaceutically acceptable water-soluble polymer and atleast one pharmaceutically acceptable surfactant. In one embodiment, thepharmaceutically acceptable water-soluble polymer has a glass transitiontemperature (Tg) of at least about 50° C.

The term “solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed evenly throughout theother component or components. For example, the active ingredient orcombination of active ingredients is dispersed in a matrix comprised ofthe pharmaceutically acceptable water-soluble polymer(s) andpharmaceutically acceptable surfactant(s). The term “solid dispersion”encompasses systems having small particles, typically of less than 1 μmin diameter, of one phase dispersed in another phase. When saiddispersion of the components is such that the system is chemically andphysically uniform or homogenous throughout or consists of one phase (asdefined in thermodynamics), such a solid dispersion will be called a“solid solution” or a “glassy solution”. A glassy solution is ahomogeneous, glassy system in which a solute is dissolved in a glassysolvent. Glassy solutions and solid solutions of HIV protease inhibitorsare preferred physical systems. These systems do not contain anysignificant amounts of active ingredients in their crystalline ormicrocrystalline state, as evidenced by thermal analysis (DSC) or X-raydiffraction analysis (WAXS).

In one embodiment of the present invention, the pharmaceutical dosageform is comprising from about 5 to about 30% by weight of the totaldosage form (preferably from about 10 to about 25% by weight of thetotal dosage form) of an HIV protease inhibitor or a combination of HIVprotease inhibitors, from about 50 to about 85% by weight of the totaldosage form (preferably from about 60 to about 80% by weight of thetotal dosage form) of a water-soluble polymer (or any combination ofsuch polymers), from about 2 to about 20% by weight of the total dosageform (preferably from about 3 to about 15% by weight of the total dosageform) of the surfactant (or combination of surfactants), and from about0 to about 15% by weight of the total dosage form of additives.

HIV protease inhibiting compounds suitable for use in the presentinvention include for example, but are not limited thereto:

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valinyl)amino-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-amino-1,6-diphenyl-3hydroxyhexane(ritonavir);

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl]-amino-1,6-diphenylhexane(ABT-378; lopinavir);

N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide(indinavir);

N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide(saquinavir);

5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide;

1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4t-butylamide;

5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-tbutylamide;

[1S-[1R-(R-),2S*])-N¹[3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylpropyl)amino]-2hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide;

amprenavir (VX-478); DMP-323; DMP-450; AG1343 (nelfinavir);

atazanavir (BMS 232,632);

tipranavir;

palinavir;

TMC-114;

RO033-4649;

fosamprenavir (GW433908);

P-1946;

BMS 186,318; SC-55389a; BILA 1096 BS; and U-140690, or combinationsthereof.

In one embodiment, ritonavir (Abbott Laboratories, Abbott Park, Ill.,USA) is an HIV protease inhibitor which may be formulated into thedosage form of the invention. This and other compounds as well asmethods for preparing same are disclosed in U.S. Pat. Nos. 5,542,206 and5,648,497, the disclosures of which are herein incorporated byreference. In a further embodiment, the present invention provides adosage form wherein said HIV protease inhibitor is ritonavir or acombination of ritonavir and at least one other HIV protease inhibitor,the dosage form showing a dose-adjusted AUC of ritonavir plasmaconcentration in dogs of at least about 9 μg·h/ml/100 mg.

In another embodiment, lopinavir (Abbott Laboratories, Abbott Park,Ill., USA) is an HIV protease inhibitor which may be formulated into thedosage form of the invention. This and other compounds, as well asmethods for preparing same, are identified in U.S. Pat. No. 5,914,332,the disclosure of which is herein incorporated by reference. In afurther embodiment, the present invention provides a dosage form whereinsaid HIV protease inhibitor is lopinavir or a combination of lopinavirand at least one other HIV protease inhibitor, the dosage form showing adose-adjusted AUC of lopinavir plasma concentration in dogs of at leastabout 20 μg·h/ml/100 mg (preferably at least about 22.5 μg·h/ml/100 mg,most preferred at least about 35 μg·h/ml/100 mg).

In yet another embodiment, nelfinavir mesylate (marketed under thetradename Viracept by Agouron Pharmaceuticals, Inc. in La Jolla, Calif.)is an HIV protease inhibitor which may be formulated into the dosageform of the invention.

The dosage forms of the present invention exhibit a release andabsorption behaviour that is characterized by high attainable AUC, highattainable C_(max) (maximum plasma concentration), and low T_(max) (timeto reach maximum plasma concentration).

In still another embodiment, the present invention provides a dosageform wherein said HIV protease inhibitor is a combination of ritonavirand lopinavir, the dosage form showing a dose-adjusted AUC of ritonavirplasma concentration in dogs of at least about 9 μg·h/ml/100 mg and adose-adjusted AUC of lopinavir plasma concentration of at least about 20μg·h/ml/100 mg (preferably at least about 22.5 μg·h/ml/100 mg, mostpreferred at least about 35 μg·h/ml/100 mg).

The term “AUC” means “Area Under the Curve” and is used in its normalmeaning, i. e. as the area under the plasma concentration-time curvefrom 0 to 24 hours, where the dosage form has been administered orallyto dogs (beagle) under non-fasting conditions. “Non-fasting condition”means that the dogs receive a nutritionally balanced daily ration duringthe pre-test period and the whole test period. The AUC has units ofconcentration times time. Once the experimental concentration-timepoints have been determined, the AUC may conveniently be calculated, e.g. by a computer program or by the trapezoidal method. All AUC dataherein were dose adjusted to the 100 mg dose level. For the purposesherein, the AUC is determined within a dose range where the AUCincreases proportionally with dose. Administration of 50 mg ritonavir or200 mg lopinavir, respectively, to dogs is considered suitable fordetermining the AUC values as used herein.

The dosage forms according to the invention are characterized by anexcellent stability and, in particular, exhibit high resistance againstrecrystallization or decomposition of the active ingredient(s). Thus,upon storage for 6 weeks at 40° C. and 75% humidity (e.g., when kept inhigh density polyethylene (HDPE) bottles without desiccant), the dosageforms according to the present invention usually do not exhibit any signof crystallinity (as evidenced by DSC or WAXS analysis) and contain atleast about 98% of the initial active ingredient content (as evidencedby HPLC analysis).

The term “pharmaceutically acceptable surfactant” as used herein refersto a pharmaceutically acceptable non-ionic surfactant. In oneembodiment, the dosage form is comprising at least one surfactant havingan hydrophilic lipophilic balance (HLB) value of from about 4 to about10, preferably from about 7 to about 9. The HLB system (Fiedler, H. B.,Encylopedia of Excipients, 5^(th) ed., Aulendorf:ECV-Editio-Cantor-Verlag (2002)) attributes numeric values tosurfactants, with lipophilic substances receiving lower HLB values andhydrophilic substances receiving higher HLB values. Surfactants havingan HLB value of from about 4 to about 10 suitable for use in the presentinvention include for example, but are not limited thereto:

polyoxyethylene alkyl ethers, e.g. polyoxyethylene (3) lauryl ether,polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether,polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers,e.g. polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3)nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether,polyoxyethylene (3) octylphenyl ether;

polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate,PEG-300 dioleate;

alkylene glycol fatty acid mono esters, e.g. propylene glycolmonolaurate (Lauroglycol®);

sucrose fatty acid esters, e.g. sucrose monostearate, sucrosedistearate, sucrose monolaurate, sucrose dilaurate; or

sorbitan fatty acid mono esters such as sorbitan mono laurate (Span®20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), or sorbitanstearate, or

mixtures of one or more thereof.

The sorbitan mono fatty acid esters are preferred, with sorbitan monolaurate and sorbitan monopalmitate being particularly preferred.

Besides the surfactant having an HLB value of from about 4 to about 10,the dosage form may comprise additional pharmaceutically acceptablesurfactants such as polyoxyethylene castor oil derivates, e.g.polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil(Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate suchas polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40) orpolyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); orblock copolymers of ethylene oxide and propylene oxide, also known aspolyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropyleneglycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer®237, Poloxamer® 388, Poloxamer® 407 (BASF Wyandotte Corp.); or a monofatty acid ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene(20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitanmonostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate(Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20).

Where such additional surfactants are used, the surfactant having an HLBvalue of from about 4 to about 10 generally accounts for at least about50% by weight, preferably at least about 60% by weight, of the totalamount of surfactant used.

The water-soluble polymer employed in the present invention has a Tg ofat least about 50° C., preferably at least about 60° C., most preferredfrom about 80° C. to about 180° C. Methods for determining Tg values ofthe organic polymers are described in “Introduction to Physical PolymerScience”, 2nd Edition by L. H. Sperling, published by John Wiley & Sons,Inc., 1992. The Tg value can be calculated as the weighted sum of the Tgvalues for homopolymers derived from each of the individual monomers,i.e., that make up the polymer: Tg=ΣW_(i)X_(i) where W is the weightpercent of monomer i in the organic polymer, and X is the Tg value forthe homopolymer derived from monomer i. Tg values for the homopolymersmay be taken from “Polymer Handbook”, 2nd Edition by J. Brandrup and E.H. Immergut, Editors, published by John Wiley & Sons, Inc., 1975.

Water-soluble polymers having a Tg as defined above allow for thepreparation of solid dispersions that are mechanically stable and,within ordinary temperature ranges, sufficiently temperature stable sothat the solid dispersions may be used as dosage forms without furtherprocessing or be compacted to tablets with only a small amount oftabletting aids.

The water-soluble polymer comprised in the dosage form is a polymer thatpreferably has an apparent viscosity, when dissolved at 20° C. in anaqueous solution at 2% (w/v), of about 1 to about 5000 mPa·s. morepreferably of about 1 to about 700 mPa·s, and most preferred of about 5to about 100 mPa·s. Water-soluble polymers suitable for use in thepresent invention include for example, but are not limited thereto:

homopolymers and copolymers of N-vinyl lactams, escpecially homopolymersand copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone (PVP),copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate,

cellulose esters and cellulose ethers, in particular methylcellulose andethylcellulose, hydroxyalkylcelluloses, in particularhydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particularhydroxypropylmethylcellulose, cellulose phthalates or succinates, inparticular cellulose acetate phthalate and hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose succinate orhydroxypropylmethylcellulose acetate succinate;

high molecular polyalkylene oxides such as polyethylene oxide andpolypropylene oxide and copolymers of ethylene oxide and propyleneoxide,

polyacrylates and polymethacrylates such as methacrylic acid/ethylacrylate copolymers, methacrylic acid/methyl methacrylate copolymers,butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers,poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),

polyacrylamides,

vinyl acetate polymers such as copolymers of vinyl acetate and crotonicacid, partially hydrolyzed polyvinyl acetate (also referred to aspartially saponified “polyvinyl alcohol”),

polyvinyl alcohol,

oligo- and polysaccharides such as carrageenans, galactomannans andxanthan gum, or mixtures of one or more thereof.

Of these, homopolymers or copolymers of N-vinyl pyrrolidone, inparticular a copolymer of N-vinyl pyrrolidone and vinyl acetate, arepreferred. A particularly preferred polymer is a copolymer of about 60%by weight of the copolymer, N-vinyl pyrrolidone and about 40% by weightof the copolymer, vinyl acetate.

The dosage forms of the invention may contain at least one conventionaladditive, such as flow regulators, lubricants, bulking agents (fillers)and disintegrants. In general, the additive is contained in an amount ofabout 0.01 to about 15% by weight relative to the weight of the dosageform.

Various methods can be used for manufacturing the solid dosage formsaccording to the invention. These methods comprise the preparation of asolid solution of the HIV protease inhibitor or the combination of HIVprotease inhibitors in a matrix of the water-soluble polymer and thesurfactant, and shaping into the required tablet form. Alternatively,the solid solution product may be subdivided to granules, e.g. bygrinding or milling, and the granules may subsequently be compacted totablets.

Various techniques exist for preparing solid solutions includingmelt-extrusion, spray-drying and solution-evaporation withmelt-extrusion being preferred.

The melt-extrusion process comprises the steps of preparing ahomogeneous melt of the HIV protease inhibitor or the combination of HIVprotease inhibitors, the water-soluble polymer and the surfactant, andcooling the melt until it solidifies. “Melting” means a transition intoa liquid or rubbery state in which it is possible for one component toget embedded homogeneously in the other. Typically, one component willmelt and the other components will dissolve in the melt thus forming asolution. Melting usually involves heating above the softening point ofthe water-soluble polymer. The preparation of the melt can take place ina variety of ways. The mixing of the components can take place before,during or after the formation of the melt. For example, the componentscan be mixed first and then melted or be simultaneously mixed andmelted. Usually, the melt is homogenized in order to disperse the activeingredients efficiently. Also, it may be convenient first to melt thewater-soluble polymer and then to mix in and homogenize the activeingredients.

Usually, the melt temperature is in the range of about 70 to about 250°C., preferably from about 80 to about 180° C., most preferred from about100 to about 140° C.

The active ingredients can be employed as such or as a solution ordispersion in a suitable solvent such as alcohols, aliphatichydrocarbons or esters. Another solvent which can be used is liquidcarbon dioxide. The solvent is removed, e.g. evaporated, uponpreparation of the melt.

Various additives may be included in the melt, for example flowregulators such as colloidal silica; lubricants, fillers, disintegrants,plasticizers, stabilizers such as antioxidants, light stabilizers,radical scavengers, stabilizers against microbial attack.

The melting and/or mixing takes place in an apparatus customary for thispurpose. Particularly suitable ones are extruders or kneaders. Suitableextruders include single screw extruders, intermeshing screw extrudersor else multiscrew extruders, preferably twin screw extruders, which canbe corotating or counterrotating and, optionally, be equipped withkneading disks. It will be appreciated that the working temperatureswill also be determined by the kind of extruder or the kind ofconfiguration within the extruder that is used. Part of the energyneeded to melt, mix and dissolve the components in the extruder can beprovided by heating elements. However, the friction and shearing of thematerial in the extruder may also provide a substantial amount of energyto the mixture and aid in the formation of a homogeneous melt of thecomponents.

The melt ranges from pasty to viscous. Shaping of the extrudateconveniently is carried out by a calender with two counter-rotatingrollers with mutually matching depressions on their surface. A broadrange of tablet forms can be attained by using rollers with differentforms of depressions. Alternatively, the extrudate is cut into pieces,either before (hot-cut) or after solidification (cold-cut).

Optionally, the resulting solid solution product is milled or ground togranules. The granules may then be compacted. Compacting means a processwhereby a powder mass comprising the granules is densified under highpressure in order to obtain a compact with low porosity, e.g. a tablet.Compression of the powder mass is usually done in a tablet press, morespecifically in a steel die between two moving punches. Where a soliddosage form of the invention comprises a combination of more than oneHIV protease inhibitor (or a combination of an HIV protease inhibitorwith one or more other active ingredients) it is of course possible toseparately prepare solid solution products of the individual activeingredients and to blend the milled or ground products beforecompacting.

At least one additive selected from flow regulators, disintegrants,bulking agents (fillers) and lubricants is preferably used in compactingthe granules. Disintegrants promote a rapid disintegration of thecompact in the stomach and keeps the granules which are liberatedseparate from one another. Suitable disintegrants are crosslinkedpolymers such as crosslinked polyvinyl pyrrolidone and crosslinkedsodium carboxymethylcellulose. Suitable bulking agents (also referred toas “fillers”) are selected from lactose, calcium hydrogenphosphate,microcrystalline cellulose (Avicell®), silicates, in particular siliciumdioxide, magnesium oxide, talc, potato or corn starch, isomalt,polyvinyl alcohol.

Suitable flow regulators are selected from highly dispersed silica(Aerosil®), and animal or vegetable fats or waxes.

A lubricant is preferably used in compacting the granules. Suitablelubricants are selected from polyethylene glycol (e.g., having a Mw offrom 1000 to 6000), magnesium and calcium stearates, sodium stearylfumarate, and the like.

Various other additives may be used, for example dyes such as azo dyes,organic or inorganic pigments such as aluminium oxide or titaniumdioxide, or dyes of natural origin; stabilizers such as antioxidants,light stabilizers, radical scavengers, stabilizers against microbialattack.

Dosage forms according to the invention may be provided as dosage formsconsisting of several layers, for example laminated or multilayertablets. They can be in open or closed form. “Closed dosage forms” arethose in which one layer is completely surrounded by at least one otherlayer. Multilayer forms have the advantage that two active ingredientswhich are incompatible with one another can be processed, or that therelease characteristics of the active ingredient(s) can be controlled.For example, it is possible to provide an initial dose by including anactive ingredient in one of the outer layers, and a maintenance dose byincluding the active ingredient in the inner layer(s). Multilayertablets types may be produced by compressing two or more layers ofgranules. Alternatively, multilayer dosage forms may be produced by aprocess known as “coextrusion”. In essence, the process comprisespreperation of at least two different melt compositions as explainedabove, and passing these molten compositions into a joint coextrusiondie. The shape of the coextrusion die depends on the required drug form.For example, dies with a plain die gap, called slot dies, and dies withan annular slit are suitable.

In order to facilitate the intake of such a dosage form by a mammal, itis advantageous to give the dosage form an appropriate shape. Largetablets that can be swallowed comfortably are therefore preferablyelongated rather than round in shape.

A film coat on the tablet further contributes to the ease with which itcan be swallowed. A film coat also improves taste and provides anelegant appearance. If desired, the film-coat may be an enteric coat.The film-coat usually includes a polymeric film-forming material such ashydroxypropyl methylcellulose, hydroxypropylcellulose, and acrylate ormethacrylate copolymers. Besides a film-forming polymer, the film-coatmay further comprise a plasticizer, e.g. polyethylene glycol, asurfactant, e.g. a Tween® type, and optionally a pigment, e.g. titaniumdioxide or iron oxides. The film-coating may also comprise talc asanti-adhesive. The film coat usually accounts for less than about 5% byweight of the dosage form.

The exact dose and frequency of administration depends on the particularcondition being treated, the age, weight and general physical conditionof the particular patient as well as other medication the individual maybe taking, as is well known to those skilled in the art.

Exemplary compositions of the present invention for combinedadministration of ritonavir/lopinavir are shown below in Table 1, andthe values are % by weight.

TABLE 1 Ritonavir  18-22.5 4.17 4.17 Lopinavir in 16.67 16.67 totalCopovidone (N- 65-75  71.16 70.12 vinyl pyrrolidone/vinyl acetatecopolymer 60:40) Span 20 (Sorbitan 4-10 7.0 5.02 monolaurate) CremophorRH40 0-10 — 3.02 (polyoxyethyleneglycerol oxystearate) Colloidal silica0-3  1.0 1.0

Exemplary compositions of the invention for administration of ritonavironly are shown below in Table 2. The values are % by weight.

Ritonavir   18-22.5 20.8 Lopinavir — — Copovidone (N- 60-75 63.15 vinylpyrrolidone/vinyl acetate copolymer 60:40) Span 20 (Sorbitan  5-15 —monolaurate) in total Cremophor RH40 10.00 (polyoxyethyleneglyceroloxystearate) PEG 6000 0-8 5.00 Colloidal silica 0-3 1.04

The above compositions are processed by melt extrusion. The resultingextrudates may be used as such or milled and compressed into tablets,preferably by the use of suitable tabletting aids such as sodium stearylfumarate, colloidal silica, lactose, isomalt, calcium silicate, andmagnesium stearate, cellulose or calcium hydrogenphosphate.

The following examples will serve to further illustrate the inventionwithout limiting it.

Protocol for the Oral Bioavailability Studies

Dogs (beagle dogs, mixed sexes, weighing approximately 10 kg) received abalanced diet with 27% fat and were permitted water ad libitum. Each dogreceived a 100 μg/kg subcutaneous dose of histamine approximately 30minutes prior to dosing. A single dose corresponding to about 200 mglopinavir, about 50 mg ritonavir, or about 200 mg lopinavir and about 50mg ritonavir, respectively, was administered to each dog. The dose wasfollowed by approximately 10 milliliters of water. Blood samples wereobtained from each animal prior to dosing and 0.25, 0.5, 1.0, 1.5, 2, 3,4, 6, 8, 10, 12 and 24 hours after drug administration. The plasma wasseparated from the red cells by centrifugation and frozen (−30° C.)until analysis. Concentrations of HIV protease inhibitors weredetermined by reverse phase HPLC with low wavelength UV detectionfollowing liquid-liquid extraction of the plasma samples. The area underthe curve (AUC) was calculated by the trapezoidal method over the timecourse of the study. Each dosage form was evaluated in a groupcontaining 8 dogs; the values reported are averages for each group ofdogs.

COMPARATIVE EXAMPLE

Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 78.17parts by weight) was mixed with ritonavir (4.16 parts by weight),lopinavir (16.67 parts by weight) and colloidal silica (1.0 part byweight). The powdery mixture was then fed into a twin-screw extruder(screw diameter 18 mm) at a rate of 2.0 kg/h and a melt temperature of133° C. The clear, fully transparent melt was fed to a calender with twocounter-rotating rollers having mutually matching cavities on theirsurfaces. Tablets of 1080 mg were thus obtained. DSC and WAXS analysisdid not reveal any evidence of crystalline drug material in theformulation.

The dose-adjusted AUC in dogs was 0.52 μg·h/ml/100 mg for ritonavir and4.54 μg·h/ml/100 mg for lopinavir. This example shows that solidsolutions of HIV protease inhibitors without added surfactant yield avery poor bioavailabilty.

Example 1

Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 68.17parts by weight) was blended with Cremophor RH40(polyoxyethyleneglycerol oxystearate; 10.00 parts by weight) in a Diosnahigh-shear mixer. The resulting granules were mixed with ritonavir (4.17parts by weight), lopinavir (16.67 parts by weight) and colloidal silica(1.00 parts by weight). The powdery mixture was then fed into aLeistritz Micro 18 twin-screw extruder at a rate of 2.3 kg/h and a melttemperature of 126° C. The extrudate was cut into pieces and allowed tosolidify. The extruded pieces were milled using a high impact universalmill. The milled material (86.49 parts by weight) was blended in a binblender with lactose monohydrate (6.00 parts by weight), crosslinked PVP(6.00 parts by weight), colloidal silica (1.00 part by weight) andmagnesium stearate (0.51 parts by weight). The powdery, blend wascompressed to tablets of 1378.0 mg on a Fette E 1 single punch tabletpress. The tablets were then film-coated in a coating pan by spraying anaqueous dispersion for film coating (Opadry, available from Colorcon) ata temperature of 60° C.

The dose-adjusted AUC in dogs was 0.60 μg·h/ml/100 mg for ritonavir and7.43 μg·h/ml/100 mg for lopinavir. This example shows that inclusion ofa surfactant into solid solutions of HIV protease inhibitors improvesthe bioavailabilty attained.

Example 2

Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 853.8parts by weight) was blended with Span 20 (Sorbitan monolaurate; 83.9parts by weight) in a Diosna high-shear mixer. The resulting granuleswere mixed with ritonavir (50 parts by weight), lopinavir (200 parts byweight) and colloidal silica (12 parts by weight). The powdery mixturewas then fed into a twin-screw extruder (screw diameter 18 mm) at a rateof 2.1 kg/h and a melt temperature of 119° C. The extrudate was fed to acalender with two counter-rotating rollers having mutually matchingcavities on their surfaces. Tablets of 1120 mg were thus obtained.

The dose-adjusted AUC in dogs was 10.88 μg·h/ml/100 mg for ritonavir and51.2 μg·h/ml/100 mg for lopinavir. This example shows that inclusion ofa surfactant having an HLB of 4 to 10 into solid solutions of HIVprotease inhibitors markedly improves the bioavailability attained.

Example 3

Example 2 was repeated, however, the extrudate was cut into pieces andallowed to solidify. The extruded pieces were milled to a particle sizeof about 250 μm, using a high impact universal mill. The milled materialwas blended in a bin blender with sodium stearyl fumarate (12.3 parts byweight) and colloidal silica (8.0 parts by weight) for 20 min. Thepowdery blend was compressed on a rotary tablet machine with 3 punches(6500 tablets/h). The tablets were then film-coated in a coating pan byspraying an aqueous dispersion for film coating (Opadry) at atemperature of 60° C.

The dose-adjusted AUC in dogs was 14.24 μg·h/ml/100 mg for ritonavir and52.2 μg·h/ml/100 mg for lopinavir.

Example 4

Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 841.3parts by weight) was blended with Cremophor RH40(polyoxyethyleneglycerol oxystearate; 36.2 parts by weight), Span 20(Sorbitan monolaurate; 60.2 parts by weight) in a Diosna high-shearmixer. The resulting granules were mixed with ritonavir (50 parts byweight), lopinavir (200 parts by weight) and colloidal silica (12 partsby weight). The powdery mixture was then fed into a twin-screw extruder(screw diameter 18 mm) at a rate of 2.1 kg/h and a melt temperature of114° C. The extrudate was fed to a calender with two counter-rotatingrollers having mutually matching cavities on their surfaces. Tablets of1120 mg were thus obtained.

The dose-adjusted AUC in dogs was 10.96 μg·h/ml/100 mg for ritonavir and46.5 μg·h/ml/100 mg for lopinavir. This example shows that a combinationof a surfactant having an HLB of 4 to 10 and a further surfactant cansuccessfully be used.

Example 5

Example 4 was repeated, however, the extrudate was cut into pieces andallowed to solidify. The extruded pieces were milled to a particle sizeof about 250 μm, using a high impact universal mill. The milled materialwas blended in a bin blender with sodium stearylfumarate (13.9 parts byweight), colloidal silica (7.0 parts by weight), isomalt DC100 (159.4parts by weight) and calcium silicate (7.0 parts by weight) for 20 min.The blend was compressed and film-coated as described in example 1.

The dose-adjusted AUC in dogs was 10.38 μg·h/ml/100 mg for ritonavir and42.7 μg·h/ml/100 mg for lopinavir.

Example 6

Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 683.3parts by weight) was blended with Span 40 (sorbitan monopalmitate; 67.2parts by weight) in a Diosna high-shear mixer. The resulting granuleswere mixed with lopinavir (200 parts by weight) and colloidal silica(9.6 parts by weight). The powdery mixture was then fed into atwin-screw extruder (screw diameter 18 mm) at a rate of 2.1 kg/h and amelt temperature of 119° C. The extrudate was cut into pieces andallowed to solidify. The extruded pieces were milled using a high impactuniversal mill. The milled material was blended in a bin blender withsodium stearylfumarate (7.9 parts by weight), colloidal silica (11.3parts by weight), isomalt DC100 (129.1 parts by weight) and sodiumdodecyl sulfate (15.6 parts by weight). The blend was compressed andfilm-coated as described in example 1.

Tablets corresponding to 200 mg lopinavir were coadministered to dogstogether with 50 mg ritonavir. The dose-adjusted AUC of lopinavir was38.8 μg·h/ml/100 mg.

Example 7

Copovidone (N-vinyl pyrrolidone/vinyl acetate copolymer 60:40; 151.5parts by weight) was blended with Cremophor RH40 (24 parts by weight)and PEG 6000 (12 parts by weight) in a Diosna high-shear mixer. Theresulting granules were mixed with ritonavir (50 parts by weight) andcolloidal silica (2.4 parts by weight). The powdery mixture was then fedinto a twin-screw extruder and was melt-extruded. The extrudate was cutinto pieces and allowed to solidify. The extruded pieces were milledusing a high impact universal mill. The milled material was blended in abin blender with colloidal silica (1.4 parts by weight), isomalt DC100(31.9 parts by weight) and calcium silicate (4.2 parts by weight). Theblend was compressed and film-coated as described in example 1.

The dose-adjusted AUC in dogs was 9.98 μg·h/ml/100 mg.

1. A solid pharmaceutical dosage form comprising a solid dispersionwhich includes: lopinavir and ritonavir; a pharmaceutically acceptablewater-soluble polymer having a Tg of at least 50° C., and apharmaceutically acceptable surfactant having an HLB value of from 4 to10.
 2. The dosage form of claim 1, wherein said surfactant is a sorbitanfatty acid ester.
 3. The dosage form of claim 1, wherein saidwater-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinylacetate.
 4. The dosage form of claim 1, wherein said water-solublepolymer is copovidone.
 5. The dosage form of claim 1, wherein saidwater-soluble polymer is a copolymer of N-vinyl pyrrolidone and vinylacetate, and said surfactant is a sorbitan fatty acid ester.
 6. Thedosage form of claim 1, wherein said solid dispersion is a solidsolution or a glassy solution.
 7. The dosage form of claim 5, whereinsaid solid dispersion is a solid solution or a glassy solution.
 8. Thedosage form of claim 1, wherein said water-soluble polymer has a Tg offrom 80 to 180° C.
 9. The dosage form of claim 1, wherein said dosageform has a dose-adjusted AUC, in dogs under non-fasting conditions, ofritonavir plasma concentration of at least 9 μg h/ml/100 mg, and adose-adjusted AUC, in dogs under non-fasting conditions, of lopinavirplasma concentration of at least 20 μg h/ml/100 mg.
 10. The dosage formof claim 1 which contains, upon storage for 6 weeks at 40° C. and 75%humidity, at least 98% of the initial content of ritonavir.
 11. Thedosage form of claim 1, wherein said dosage form comprises from 50 to85% by weight of the total dosage form of said water-soluble polymer,and from 2 to 20% by weight of the total dosage form of said surfactant.12. A solid pharmaceutical dosage form comprising: lopinavir andritonavir formulated in solid dispersion, wherein said solid dispersioncomprise (1) a pharmaceutically acceptable water-soluble polymer havinga Tg of at least 50° C., or a combination of pharmaceutically acceptablewater-soluble polymers having a Tg of at least 50° C.; and (2) apharmaceutically acceptable surfactant having an HLB value of from 4 to10, or a combination of pharmaceutically acceptable surfactants havingan HLB value of from 4 to
 10. 13. The dosage form of claim 12, whereinsaid solid dispersion comprises a combination of pharmaceuticallyacceptable water-soluble polymers having a Tg of at least 50° C.
 14. Thedosage form of claim 12, wherein said solid dispersion comprises acombination of pharmaceutically acceptable surfactants which has an HLBvalue of from 4 to
 10. 15. The dosage form of claim 12, wherein saidsolid dispersion is solid solution or glassy solution.
 16. The dosageform of claim 12, wherein said dosage form has a dose-adjusted AUC, indogs under non-fasting conditions, of ritonavir plasma concentration ofat least 9 μg h/ml/100 mg, and a dose-adjusted AUC, in dogs undernon-fasting conditions, of lopinavir plasma concentration of at least 20μg h/ml/100 mg.
 17. The dosage form of claim 12 which contains, uponstorage for 6 weeks at 40° C. and 75% humidity, at least 98% of theinitial content of ritonavir.